With a 5-year survival rate of less than 4% pancreatic cancer is the fourth leading cause of cancer death in the United States. Current chemotherapy and radiation therapy are largely ineffective in the treatment of this disease. Surgical treatment offers the only hope for long term survival. Unfortunately, only ~15% of patients have resectable disease at the time of diagnosis. The 5-year survival rate for patients who have undergone a successful resection (negative surgical margin) is still sobering, varying from 5-30% in the literature. Among the reasons for this poor prognosis is perineural invasion of cancer cells into noncancerous pancreas or the retroperitoneum plexus. Perineural invasion is a feature of pancreatic cancer;up to 100% of patients show involvement of intrapancreatic nerves and >70% invade extrapancreatic nerves. This infiltration accounts for local recurrence after tumor resection. Severe abdominal and back pain is very common in patients with pancreatic cancer and correlates strongly with perineural invasion. Recent reports indicate that expression of nerve growth factor (NGF) and its receptors correlate with perineural invasion and pain in human pancreatic cancer. However, the molecular mechanisms of perineural invasion in pancreatic cancer and the role of the NGF signaling pathway are still not clear. In this project experiments will elucidate the role of NGF and its receptors in perineural invasion of pancreatic cancer and to identify additional genes/proteins that regulate perineural invasion. The central hypothesis of this project is that there exist direct communications through signaling molecules such as NGF and its receptors between pancreatic cancer cells and the nerve cells which stimulate the infiltration of cancer cells into the perineurium space. The specific aims of this project are: 1) to determine the specific role of NGF and its receptors (TrkA and p75NTR) in the invasion of pancreatic cancer cells into peripheral nerves using in vitro and ex vivo perineural invasion model systems;and 2) to discover and validate additional genes and pathways that drive perineural invasion. This will be done using DNA microarray based gene and microRNA (miRNA) expression profiling of microdissected nerve cells, stroma cells and pancreatic cancer cells within nerve bundles. The goal of this research is to understand the molecular mechanisms of neural invasion by pancreatic cancer and identify molecular targets for the development of therapeutics that may prevent neural invasion. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is the fourth leading course of cancer death in the United States. Even with treatment, the medium survival for pancreatic cancer patients is 6 months and the 5-year survival rate is less than 4%. One of the main reasons for this dismal prognosis of the disease is its highly invasive and metastatic nature. Perineural invasion is one of the most common features of pancreatic cancer and it causes pain. This pain has a tremendous impact on the patient quality of life ad it is very difficult to manage. Reasons for the high affinity of pancreatic cancer cells for neural tissues are not clear. The current proposal seeks to investigate the molecular mechanisms of neural invasion in pancreatic cancer and identify new molecular targets for the development of therapeutics that may prevent neural invasion. The results generated in this proposal therefore have the potential to directly benefit pancreatic cancer patients with improved treatment.